Molecular Stable Structure Search Using Probability Distribution Functions
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Solution Overview
Problem
Current methods for predicting the three-dimensional structure of compounds, especially cyclic peptides, face challenges in determining the most stable and metastable structures due to the requirement for measurement results and high computation time, making it difficult to predict drug activity and cell membrane permeability before synthesis.
Innovation Solution
A method that generates three-dimensional structures from a structural formula, calculates energy distribution and probability distribution functions, and repeatedly adjusts internal coordinates to increase the likelihood of low-energy structures, allowing for the acquisition of most stable and locally stable structures in a shorter time with higher accuracy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If local structural deformation simulating thermal fluctuation is performed to obtain stable conformers, then three-dimensional structure prediction is achieved, but computation time becomes enormous
Solution Approach 1:
The patent changes the approach from simulating thermal fluctuation through local structural deformation to directly generating three-dimensional structures by randomly setting internal coordinates. This parameter change in the search method fundamentally reduces computation time while maintaining prediction accuracy for cyclic peptide structures.
Solution Approach 2:
The patent segments the conformational search process into two distinct phases: (1) generating initial three-dimensional structures by randomly setting internal coordinates, and (2) obtaining locally stable structures through energy minimization. This segmentation allows efficient exploration of conformational space without the enormous computation time required by continuous thermal fluctuation simulation.
2Measurement precision
If NMR measurement results are required to determine three-dimensional structure, then structure prediction accuracy is improved, but applicability to compounds without measurement results is lost
Solution Approach 1:
The patent enables the system to perform self-service structure prediction using only the structural formula as input. By randomly setting internal coordinates and obtaining locally stable structures through energy minimization, the system independently determines three-dimensional structures without requiring external NMR measurement results or other experimental data, thereby achieving both accuracy and versatility.
3Reliability
If conformational search is performed by local structural deformation, then stable conformers are obtained, but the most stable structure requires enormous time to be found through multiple metastable structures
Solution Approach 1:
The patent performs preliminary action by randomly setting internal coordinates to generate initial three-dimensional structures before energy minimization. This preliminary structure generation step efficiently explores conformational space and provides multiple starting points for obtaining locally stable structures, significantly reducing the time required to identify the most stable structure compared to sequential energy minimization from a single starting structure.
Data Source
AI summary
Provided are a method for searching for a molecular stable structure, a program for searching for a molecular stable structure, and a device for searching for a molecular stable structure, which are capable of acquiring a stable structure and various locally stable structures from a structural formula of a compound in a short time and with high accuracy. A three-dimensional structure is generated from the structural formula of the compound, and a locally stable structure is obtained from the three-dimensional structure. A one-dimensional or multidimensional energy distribution function for one or a plurality of internal coordinates and a probability distribution function of increasing a probability of low-energy internal coordinates are calculated from internal coordinates and an energy value of the locally stable structure. The method for searching for a molecular stable structure repeats the following processes: generating a three-dimensional structure based on the calculated probability distribution function; acquiring a locally stable structure; reflecting internal coordinates and an energy value of the obtained locally stable structure on the energy distribution function and the probability distribution function; and acquiring the locally stable structure, thereby obtaining a plurality of the locally stable structures and a structure with lowest energy. The program and the device for searching for a molecular stable structure execute the method.